Viruses can use a number of strategies including escape from immune recognition or induction of immunosuppression to avoid immunological surveillance and thereby persist in the host. Elucidating the mechanisms by which viruses persist and escape immune surveillance is important to our understanding of viral pathogenesis and for the development of measures to control and eliminate such infections and the diseases they cause. Viral persistence following infection with invasive strains of lymphocytic choriomeningitis virus (LCMV) can be achieved by selective down-regulation ("clonal exhaustion") of the virus-specific T cell mediated response in a host with a mature immune system. In this scenario, high viral burden at the onset of infection drives responding cytotoxic CD8+ T cells (CTLs) into different programs of exhaustion such as induction of anergy (functional unresponsiveness) and/or deletion. This dampening of virus-specific CD8+ T cell responses in the early phase of infection results in a protracted or permanent persistence of infection. Tolerance by "clonal exhaustion" also affects virus specific CD4+ T cells and their functional inactivation can promote a permanent persistence of the viral infection. In this proposal, we wish to extend our previous findings by specifically focusing on molecular mechanisms underlining "clonal exhaustion" of virus-specific T cells in a mature host. The specific aims are the following: (1) To dissect specific viral determinants playing a role in establishment of a persistent viral infection by "clonal exhaustion" of virus-specific T cells. (2) To examine the contribution of antigen presenting cell interactions with T cells to the "clonal exhaustion" of virus-specific T cells in mice with a persistent LCMV infection. (3) To examine molecular mechanisms in T cell receptor signaling that induce virus-specific T-cell anergy and/or deletion during chronic LCMV infection of mice. Detailed insight into interaction of viruses with the immune system stands to generate concepts for more adequate vaccine and therapeutic strategies and will also help us to better understand the immune system.